Microfluidics in Medicine

A microfluidic chip devised to separate cancer cells from blood cells by engineers at the University of Michigan Ann Harbor. Image courtesy of  The Engineer .

A microfluidic chip devised to separate cancer cells from blood cells by engineers at the University of Michigan Ann Harbor. Image courtesy of The Engineer.

Author: Christine Hirschberger Edited by: Burcu Anil Kirmizitas

Straddling both science and technology, microfluidics has long been hailed as the upcoming revolutioniser of the ways we do chemical synthesis, biological analysis and even optics and information technology. The miniaturisation of conventional laboratory technologies and equipment through microfluidics has led to stunning advancements such as minimising reagent use and maximising information gained from small sample sizes, simplifying and shortening assay protocols, improving screening approaches, increasing parallel processing of samples, and, perhaps most importantly, precise spatiotemporal control of the microenvironments of cells. Microfluidics technologies have not only streamlined large areas of biological benchwork but also made great promises in various pharmaceutical and medical fields, from cancer treatments to infectious disease diagnostics to artificial organs.

Microfluidics describes the manipulation of fluids at the submillimetre scale inside hollow microfluidic channels. It is by nature highly interdisciplinary, combining elements of engineering, physics, chemistry, biology, and nanotechnology. Based on the intermingling of these fields, the semiconductor industry and the field of micro-electromechanical systems put forward lab-on-a-chip (LoC) technologies, which first allowed the microscale manipulation of fluids that are required for microfluidics. Lab-on-a-chip ideas were first proposed in the 1990s, and their application has expanded rapidly ever since.

One of the main ways in which microfluidics has been capitalised on by medical research is as a tool for drug delivery. Conventional ways of administering drugs for therapeutic purposes are mostly oral and intravenous delivery methods. These methods necessarily come with (often considerable) distances and physical boundaries between the entry point of the drug into the body and the unhealthy area of interest. Lab-on-a-chip technology can be harnessed to sidestep this problem and increase the effectiveness and precision of drug synthesis and delivery in a number of different ways.

On the cellular level, microfluidics allows investigating the effect of chemical compounds on cells in vivo. Devices such as microfluidic gradient generators have successfully been used to test how drugs affect cells in real time, while allowing the precise regulation of drug concentrations, at lower costs than conventional methods. However, these generator devices limit drug testing to one compound at a time. This is restrictive, since in many cases multi-component therapy is more effective than the use of only one drug at a time. To combat this, high-throughput combinatorial gradient generators have been developed. These devices combine more chambers and microchannels than standard microfluidic gradient generators, allowing the manipulation of several drugs at the cellular level at once.

Microfluidics have also had an impact on drug delivery on the tissue level. Over the last ten years a variety of microfluidic methods have been developed to synthesise, form and mass-produce micro- and nanoparticles, which can be used to deliver drugs in a localised and precise manner. This has greatly increased the efficacy of conventional delivery methods and has been found to be particularly useful in the fight against cancer. Both in terms of diagnosis and treatment, sophisticated microfluidics-based synthesis of drug-loaded nanoparticles with precisely controlled characteristics such as size, composition, surface, structure and rigidity has been intensely studied. Microfluidics also allows the production of nanoparticles with better quality at higher quantities than conventional methods.

Consequently, in recent years a number of microfluidic devices and techniques have been developed which substantially changed classic nanoparticle characteristics. For instance, it is possible to generate organic (polymeric and lipid) nanoparticles that can range in particle size at a slimmer size range overall, transport more drug loads at a time, and share a greater batch-to-batch reproducibility than nanoparticles made with non-microfluidics methods. Testing these methods in mice has led to very promising results and the field is moving very quickly from research stages into pre-clinical and clinical testing. For example, it has been shown conclusively that breast cancer cells can be effectively attacked by nanoparticles that are loaded with drugs which block blood vessel growth inside the tumour and attract an anti-tumour immune response. The nanoparticles are guided into the breast cancer cells by a using an antibody specific to a cancer growth promoting protein that is excessively produced in a subset of breast cancer cells. Particularly in oncology, microfluidics methods often work in tandem, both in the production and in the application of drugs at a submillimetre level.

Microfluidics has also had a huge impact on diagnostic possibilities, especially since infectious diseases still present one of greatest challenges to science all around the globe. One stunning example of how microfluidics allow the development of new, more cost-effective procedures for the diagnosing of infectious diseases is the mChip, a cheap and portable device for blood testing. The mChip can detect an infection of HIV or syphilis within 15 minutes, at an accuracy of 99% for HIV and 94% for syphilis. It combines processing and handling of the sampled blood with the amplification and detection of the signal in a single device. Its manufacturing process is so quick that one chip can be produced every 40 seconds, at a cost of about 0.10 $ per cassette. Only about 1 microlitre of blood is required for a diagnosis. This minimises the complicated steps usually necessary for detection and diagnostics of infectious diseases, which is particularly useful in areas of the world where laboratories are less easily accessible. In more remote parts of the globe, these on-site diagnostic possibilities can substantially increase treatment rates and the health of local populations.

Other, -even more revolutionary- applications of microfluidics in medicine include organ-on-a-chip devices. These chips constitute in vitro models of human physiology, and aim to mimic entire organs. Microfluidics makes this possible by allowing the precise transport of fluids such as blood or nutrient-bearing solutions through three dimensional constructs mimicking human tissue. Typically, this involves coating glass slides with human cells to simulate an interface between tissues, or a single tissue type. Organs that have been built in vitro in this way include bones, cartilage, skin, heart, kidney and even lungs. This has allowed researchers to study, for example, the entire life cycle of the hepatitis C virus, which is notoriously difficult to observe in cultured cells. Hence, these projects aim to make research on human organs much more accessible than ever before. Organs-on-a-chip technology is also a hopeful candidate method for cutting down on the need for animal testing in drug research and on the reliance on tissue cultures that bear little resemblance to actual organ systems. However, as opposed to nanotechnology and microfluidics in drug testing and treatment, this aspect of microfluidics is moving much slower. While pharmaceutical companies have taken an interest in organ-on-a-chip technology, there are no big pipelines established yet for mass-producing these devices for clinical or pharmaceutical purposes. One of the big concerns comes from the fact that organs-on-a-chip still do not present exact replica of human organs. While they get much closer to them than more traditional methods, there is still a big gap between them and the actual physiology, biomechanics and immune responses of a living human organ. Hence, experts in the field are still hedging their bets and are working on making their devices more and more accurate, before introducing them to a mass-marketing strategy and commercialisation.

Although the field of microfluidics is still young, it has already found groundbreaking applications within biomedical research and medicine, and as more and more researchers notice its power its influence is steadily increasing. Within drug development and testing, microfluidics has carved out its own space and continues to generate stunning results. Similarly, drug delivery methods are predicted to be seriously overhauled by the advancements of microfluidics, particularly within oncology and epidemiology. Researchers are also growing more interested in using microfluidics for more challenging problems such as generating faithful copies of human organs. Nonetheless, there still remains a lot of work to be done. Microfluidics remains attractive because of the strong possibilities it opens up – but these possibilities also come with risks and unknowns, and medical research still needs to do a lot of strategising before microfluidics can be harnessed at its full power.